Augmented pulmonary responses to acute ozone exposure in obese mice: roles of TNFR2 and IL-13.

Background: Acute ozone (O(3)) exposure results in greater inflammation and airway hyperresponsiveness (AHR) in obese versus lean mice.

Objectives: We examined the hypothesis that these augmented responses to O(3) are the result of greater signaling through tumor necrosis factor receptor 2 (TNFR2) and/or interleukin (IL)-13.

Methods: We exposed lean wild-type (WT) and TNFR2-deficient (TNFR2(-/-)) mice, and obese Cpe(fat) and TNFR2-deficient Cpe(fat) mice (Cpe(fat)/TNFR2(-/-)), to O(3) (2 ppm for 3 hr) either with or without treatment with anti-IL-13 or left them unexposed.

Results: O(3)-induced increases in baseline pulmonary mechanics, airway responsiveness, and cellular inflammation were greater in Cpe(fat) than in WT mice. In lean mice, TNFR2 deficiency ablated O(3)-induced AHR without affecting pulmonary inflammation; whereas in obese mice, TNFR2 deficiency augmented O(3)-induced AHR but reduced inflammatory cell recruitment. O(3) increased pulmonary expression of IL-13 in Cpe(fat) but not WT mice. Flow cytometry analysis of lung cells indicated greater IL-13-expressing CD(4+) cells in Cpe(fat) versus WT mice after O(3) exposure. In Cpe(fat) mice, anti-IL-13 treatment attenuated O(3)-induced increases in pulmonary mechanics and inflammatory cell recruitment, but did not affect AHR. These effects of anti-IL-13 treatment were not observed in Cpe(fat)/TNFR2(-/-) mice. There was no effect of anti-IL-13 treatment in WT mice.

Conclusions: Pulmonary responses to O(3) are not just greater, but qualitatively different, in obese versus lean mice. In particular, in obese mice, O(3) induces IL-13 and IL-13 synergizes with TNF via TNFR2 to exacerbate O(3)-induced changes in pulmonary mechanics and inflammatory cell recruitment but not AHR.